Lecture 24: Synapse Elimination

During development, which process decreases the number of axons that innervates postsynaptic cells?

axonal branch trimming

What strengthens the existing innervation?

synaptic rearrangement/redistribution

What does synapse lead to?

synapse refinement

What are the purposes of synapse elimination?

• remove abnormal connectivity during development

• sharpen specificity of the connectivity

• natural consequence to remove duplicated neurons in mammalian (and other vertebrate) nervous systems

What is an example of removing abnormal connectivity during development?

connections between mossy fiber axons and Purkinje cells in the developing cerebellum but not in an adult

What is an example of sharpening specificity of connectivity?

intrinsic topographic map that matches the position of an axonal arbor to the location of the cell body in the spinal cord

What is an example of the natural consequence to remove duplicated neurons in mammalian nervous systems?

• in fly NMJs, a single motor neuron innervates a single muscle consisting of only one muscle fiber

• in mammals, the equivalent NMJ has a large number of motor neurons innervate similar number of muscles

What is the ultimate goal in terrestrial vertebrates?

converting highly overlapping connections of redundant neurons into unique circuits

What does treatment with zinc iodide osmium do?

labels axon terminals and synaptic boutons

During development, what happens to the number of synaptic boutons and the number of preganglionic axons innervating each ganglionic cell?

synaptic boutons increases and number of preganglionic axons decreases

What is divergence?

neurons project their axons to fan out to many target cells

What does synapse elimination do?

reduces fan-out axonal connections to form fan-in connections (convergence)

What does synaptic rearrangement do?

strengthens other connections by increasing the number of synapses at their remaining targets

True or False: Fan-in and Fan-out is present at developing circuits.

true

Describe the Fan-in and Fan-out at NMJ development.

• at birth, the axonal arbors are 10 times larger at birth than in adults (each muscle is innervated about 10 axons)

• within 2 weeks, the Fan-out motor units are extensively removed

• serial EM reconstruction of a single NMJ at birth shows 11 axons that innervate the NMJ

Initially, each muscle fiber receives input from several alpha motor neurons. But what happens over the course of development?

all inputs but one are lost

What is axonal atrophy?

an axon that is removed first becomes thin

What occurs during axonal branch retraction?

• axonal atrophy

• a withdrawing axon disconnects from the postsynaptic site and temporarily possesses a bulb-tipped free ending called a retraction bulb

• the withdrawing axon sheds small spherical organelles called axosomes

• axosomes are engulfed by Schwann cells

At birth, multiple axons converging onto a single NMJ are intermingled, and the extent of the ACh receptor areas occupied by each are similar. What happens by the second postnatal week?

the highly intermingled connections become segregated

True or False: There is a takeover of synaptic territory by the remaining axon during synapse elimination.

true

What is the axonal fate at each NMJ determined by?

the identity of the competing axons

True or False: When 2 axons compete, the fate is the same at each co-innervated NMJ.

true

Why can the neuron with a larger motor unit and more branches lose to a neuron with a smaller unit and less branches?

the larger axoned-neuron can over-exhaust its resources such as the amount of synaptic vesicle per synapse

True or False: Axonal branch loss is occurring asynchronously among all the branches of an axon.

true

Synapse elimination in the NMJ does not occur in postsynaptic cells that don’t what?

fire action potentials

What type of channels do twitch fibers have?

voltage-sensitive sodium channels that generate APs

How many axons innervate the NMJ in twitch fibers?

a single axon

Do tonic fibers have regenerative potentials?

no

How many innervated NMJs do tonic fibers contain?

multiple

What is snake toxin an irreversible competitive antagonist of?

nicotinic AChRs

What does Bungarus, commonly referred to as kraits, products what?

venom containing bungarotoxin

What was the main question tested in the experiments involving the NMJs?

whether postsynaptic activity is required for synapse elimination during development

What toxin was used in the NMJ experiments?

a-Bungarotoxin

At the start of the NMJ experiment, how many axons innervated the same postsynaptic cell?

two axons converged on the same postsynaptic cell

What happened when a-bungarotoxin was applied to only a small region of the NMJ?

AChRs in that region were blocked, causing loss of postsynaptic activity only at that site

What happened to AChRs at the locked site over the next few weeks?

there was a loss of AChRs at the blocked region

What happened to the presynaptic axon branch at the blocked site?

the axon branch withdrew, resulting in presynaptic loss

What conclusion can be drawn when an active axon competes with an inactive axon?

the active axon can drive elimination of the inactive axon’s synapse

What does the withdrawal of the axon bramch demonstrate?

postsynaptic inactivity can trigger elimination of a synaptic connection

What happened when all postsynaptic activity was blocked across the entire cell?

synapses were retained; there was no loss of AChRs and no axon withdrawal

Why were synapses retained when all postsynaptic activity was blocked?

because elimination depends on relative differences in activity between competing inputs, not simply the absence of activity

What is the key principle of activity-dependent synapse elimination?

less active inputs are eliminated, while more active inputs are stabilized and maintained

What role does postsynaptic activity play in synapse elimination?

postsynaptic activity is necessary for competitive synapse elimination and helps determine which synaptic inputs survive

Before birth, when all receptors are activated synchronously because motor neurons are electrically coupled, what occurs?

no synaptic destabilization

Later in development, when two inputs are activated asynchronously, what happens to the active synaptic site?

the active synaptic site is protected

Later in development, what happens to the asynchronously activated synapse?

it is not protected

What does destabilization lead to?

synapse elimination

What happens when nAChRs are blocked in all synaptic sites?

no synaptic destabilization

Before birth, why are all receptors activated synchronously?

because motor neurons are electrically coupled

During later development, how are the two inputs activated?

asynchronously

What did the studies by Hubel and Wiesel first suggest?

competition was driving synaptic reorganization in the developing mammalian brain

What do most optic nerves innervate?

the LGN in the dorsal thalamus

Prior to emergence of ocular dominance columns, eye input to the LGN segregates into what?

layers

What are eye-specific layers in the LGN caused by? When does this occur?

caused by activity-dependent synapse elimination and synaptic rearrangement, which occurs before birth in response to spontaneous neuronal discharges

True or False: There is segregation of retinal inputs to the LGN.

true

What are retinal waves? What does this lead to?

the activity of the two eyes are not correlated but instead spontaneous leading to segregation in the LGN

What is synaptic stabilization in the retina?

only retinal terminals that are active at the same time as their postsynaptic LGN target neuron are retrained

What did Hebb discover?

• wire together fire together (Hebbian modifications)

• out of sync, lose their link

Describe synapse elimination in the LGN.

• receptor fields are decreasing in size as development proceeds due to the elimination of the convergence of multiple retinal afferents onto each geniculate neuron

• at P12, multiple retinogeniculate axons are recruited as stimulation intensity increases but by P28, only 102 inputs innervate each neuron since no steps in the evoked synaptic currents are seen even though optic nerve stimulation is increased

After birth, inputs from LGN neurons serving the two eyes are what?

segregated into ocular dominance columns in the visual cortex

What is the effect of monocular deprivation later in life?

no effect, plasticity during “critical period”

What is the effect of ocular dominance on column development?

• at birth, the afferents from the 2 eyes overlap completely in layer IV

• by 6 weeks, the afferents from 2 eyes became segregated

What is the effect of monocular deprivation on column development?

• at birth, the afferent from 1 open eye dominates layer IV

• at 3 weeks, the afferent from 1 open eye expands its columns in layer IV

What effect does monocular deprivation have on column development at 6 weeks, and why?

no effect because segregation of the afferents from 2 eyes is already completed

True or False: There is synapse elimination and axonal pruning in the cerebellum during the neonatal period.

true

At birth, Purkinje cells are innervated by what?

several different climbing fibers

In adults, most Purkinje cells are innervated by what?

singly innervated by olivocerebellar climbing fiber axons (which have more branches)